Acetaminophen (chemically named N-(4-hydroxyphenyl)acetamide), also known as para-acetylaminophenol, paracetamol and N-acetyl-para-aminophenol (abbreviated as APAP), is a widely used analgesic and antipyretic drug. It is commonly used for the relief of headaches and other minor pains, and is a major ingredient in various cold and flu remedies.
Acetaminophen is the generic name of a drug found in many common brand-name over-the-counter (OTC) and prescription (Rx) products. In some products acetaminophen is the sole active ingredient (e.g., TYLENOL®), while in others it is combined with additional active ingredients, such as opioid analgesics, nasal decongestants, cough suppressants and antihistamines. Examples include combinations with oxycodone (e.g. PERCOCET®) and hydrocodone (e.g. VICODIN®). Acetaminophen is available as a tablet, capsule, liquid suspension, suppository, intravenous, and intramuscular form.
While generally safe for use at recommended doses (up to 1,000 mg per single dose and up to 4,000 mg per day for adults), acute overdoses of acetaminophen can cause serious liver injury, acute liver failure (ALF) and even death. In effect, acetaminophen-induced liver toxicity is the most prevalent cause of acute liver failure in the Western world. In addition, several drug-host interactions, such as drug viral interactions were suggested as potential causes for acetaminophen-induced liver toxicity even without exceeding the recommended dosages.
In the liver, acetaminophen is metabolized through several pathways before being eliminated from the body. One of these pathways, which involves the cytochrome P-450 systems, yields a toxic intermediate known as N-acetyl-p-benzo-quinone imine (NAPQI). Normally, this toxic metabolite is detoxified by conjugation to reduced glutathione. However, an excessive amount of acetaminophen in the liver, and accordingly excessive amounts of NAPQI, results in shortage of reduced glutathione and accumulation of the toxic metabolite. The toxic metabolite then binds to liver proteins and cause cellular injury. The amount of the accumulated toxic metabolite and the difficulty of the liver to eliminate it before it causes damage influence the extent of liver injury. NAPQI accumulation is only one of the suggested explanations for acetaminophen-induced liver toxicity.
In addition, the immune system was suggested to play a major role in the pathogenesis of the toxic effect and the liver injury. Both NK and NKT cells as well as several cytokines were suggested as important factors in this context.
Despite a number of efforts since the early 1990s to reduce the incidence of acetaminophen-related liver injury, the extent of liver failure cases reported in the medical literature indicates that liver injury from acetaminophen overdose remains a serious public health problem.
In addition to the liver, renal damage is also associated with acetaminophen consumption. In toxic amounts, acetaminophen may result in acute tubular necrosis. At therapeutic dosages, acetaminophen can be toxic in patients with risk factors such as starvation and chronic ingestion of alcohol or certain medications. Long term consumption of normal doses of acetaminophen has also been found to result in cumulative damage to the kidneys.
Many cases of acetaminophen overdose are caused unintentionally by consumers inadvertently taking more than the recommended dose. A number of factors that may contribute to acetaminophen overdose problem have been identified, including: the narrow safety margin of acetaminophen, risk factors rendering some individuals specially and specifically prone to acetaminophen-induced liver injury, such as excessive alcohol consumption and pre-existing liver disorders, insufficient public knowledge about the serious risks of acetaminophen overdose, and the availability of many different types of OTC and Rx products containing acetaminophen and possibly other active ingredients, and a variety of doses for different indications. The latter may result in the consumption of more than one acetaminophen containing product without realizing that acetaminophen is included in all of these products, and accordingly an increased risk of acetaminophen overdose. In addition, it can be difficult to recognize and diagnose the onset of liver injury.
Current treatments of acetaminophen overdose are mainly aimed at removing acetaminophen from the body and trying to replace diminished glutathione levels. Oral administration of activated charcoal can also be used to decrease absorption of acetaminophen by binding any drug remaining in the gastrointestinal tract. The treatment also includes administration of an antidote, N-acetylcysteine (NAC), which is a known precursor for glutathione, thereby helping the body to regenerate reduced glutathione and prevent or reduce damage to the liver. A liver transplant is sometimes required if damage to the liver becomes severe and irreversible.
The known treatments have several drawbacks, mainly due to their limited therapeutic window. Actions such as gastric lavage or administration of activated charcoal are effective only in cases where the patients present for treatment soon after taking the overdose. NAC is considered effective only when administered within 8 hours following intoxication, after which the efficacy is significantly reduced.
Patients with acute overdose, or with liver toxicity due to any dose, can deteriorate into fulminant liver failure. Although some of these patients will recover spontaneously, for some of them, liver transplantation is the only way to prevent deterioration and death.
There are currently no commercially available formulations of acetaminophen which purposely intended to reduce the risk of liver toxicity.
U.S. Pat. No. 4,868,114 discloses a method comprising stimulating the biosynthesis of glutathione in mammalian cells by contacting the cells with an effective amount of cysteine prodrugs.
U.S. Pat. No. 6,555,141 discloses therapeutic compositions for the protection, treatment and repair of liver tissue comprising two or more compounds selected from the group consisting of S-adenosylmethionine, L-ergothioneine, and a compound selected from the group consisting of Milk thistle (Silybum marianum), silymarin and active components of silymarin, whether naturally, synthetically, or semi-synthetically derived, and to methods of preventing and treating liver disease and of repairing damaged liver tissue.
U.S. Pat. No. 6,566,401 discloses pharmaceutical compositions for the treatment or prevention of the toxic effects of therapeutic agents and methods of treating or preventing such toxicity using a toxicity reducing amount of N-acetylcysteine either alone or in combination with a therapeutically effective amount or, to achieve its therapeutic advantages, an amount larger than what is customarily given as a therapeutically effective amount, of a therapeutic agent.
U.S. Pat. No. 7,238,373 discloses a nutritional supplement that is designed to provide nutritional benefits as well as to assist the body with detoxification.
U.S. Pat. No. 8,148,356 discloses acetylcysteine compositions in solution, comprising acetylcysteine and which are substantially free of metal chelating agents, such as EDTA. Further, this invention relates to methods of making and using the acetylcysteine compositions. The present compositions and methods are designed to improve patient tolerance and compliance, while at the same time maintaining the stability of the pharmaceutical formulation. The compositions and methods of this invention are useful in the treatment of acetaminophen overdose, acute liver failure, various cancers, methacrylonitrile poisoning, reperfusion injury during cardio bypass surgery, and radiocontrast-induced nephropathy, and can also be used as a mucolytic agent.
US 2011/0124718 discloses the reduction of acetaminophen toxicity by dietary milk thistle extract. Milk thistle and acetaminophen are combined to provide single dosages containing both ingredients, whether dispensed in a liquid suspension, chewable tablets, coated caplets, gelcaps, geltabs, and suppositories.
US 2012/0022161 discloses a pharmaceutical composition and method for providing a reduction in side effects for human patients in need of therapy comprising the administration of a pharmaceutical composition comprising acetylcysteine.
WO 2009/097874 discloses compositions comprising a combination of amino acids selected from: a) L-Cysteine with L-Methionine; b) L-Cysteine with L-Serine; c) L-Cysteine with L-Methionine and L-Serine; d) L-Methionine with L-Serine; or precursors or transporters of said amino acids, for the prevention of paracetamol-induced liver damage.
WO 2011/044230 discloses methods and compositions comprising N-acetylcysteine amide (NAC amide) and derivatives thereof for use in treatments and prophylactic therapies for human and non-human mammalian diseases, disorders, conditions and pathologies associated with bomb blast or other high energy noise or impulse blasts. Pharmaceutically or physiologically acceptable compositions of NAC amide or derivatives thereof are also provided, which may be administered alone, or in combination with other suitable agents.
Polyak et al. (2010) PNAS U.S.A, 107; (5995-5999), report the identification of hepatoprotective flavonolignans from silymarin.
There still remains an unmet need for more effective compositions and methods for treating or preventing drug toxicity, e.g. liver damage caused by acetaminophen. There is a further need for novel compositions of acetaminophen characterized by decreased risk of inducing toxicity while preserving efficacy. Such compositions may be useful for reducing or even preventing acetaminophen-related toxicity.